Methods for the preparation of intermediates in the synthesis of HIV-protease inhibitors

ABSTRACT

Methods for the preparation of chemical intermediates in the synthesis of HIV-protease inhibitors related to and including nelfinavir mesylate are disclosed. The method of this invention comprises converting tetrohydran derivatives into oxazolines to provide key reaction intermediates for the preparation of nelfinavir. Also disclosed is a method for the preparation of a chiral amino alcohol from an epoxy-tetrahydrofuran.

[0001] This application claims benefit of the filing date of U.S.Provisional Patent Application No. 60/160,695, the disclosure of whichis incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to chemical methods of preparingintermediates in the synthesis of the protease inhibitor nelfinavirmesylate and its free base, which is useful for treatment of HIVinfected individuals.

[0004] 2. Related Background Art

[0005] Treatment of HIV-infected individuals with HIV-proteaseinhibitors has emerged as an important method for preventing orinhibiting the rapid proliferation of the virus in human tissue.HIV-protease inhibitors block a key enzymatic pathway in the virusresulting in substantially decreased viral loads, which slows the steadydecay of the immune system and its resulting deleterious effects onhuman health. The HIV-protease inhibitor nelfinavir mesylate has shownto be an effective treatment for HIV-infected individuals. Nelfinavirmesylate, and a method for its preparation are disclosed in U.S. Pat.No. 5,484,926, which is incorporated herein by reference.

[0006] Other procedures for the preparation of nelfinavir mesylate andits free base have been reported. For example, PCT/JP96/02756(WO97/11937) discloses the preparation of nelfinavir mesylate and itsfree base using oxazoline intermediates, which may be obtained from a1,3-dioxepan-5-ol, or a derivative thereof. PCT/JP96/02757 (WO97/11938)discloses a related method, wherein the 1,3-dioxepan-5-ol is convertedto nelfinavir mesylate and its free base viaN-benzyloxycarbonyl-amino-butane diol intermediates. Each of thesemethods reportedly provide some improvement in the efficiency of thepreparation of nelfinavir. However, further improvement would bedesirable.

SUMMARY OF THE INVENTION

[0007] This invention relates to efficient and cost-effective methodsfor the preparation of nelfinavir mesylate and its free base.Specifically, the methods of this invention comprise the preparation ofan oxazoline,

[0008] from a tetrahydrofuran

[0009] comprising treating the tetrahydrofuran, wherein R_(a) is —COR(1)and R_(b) is hydrogen, —COR(3), —SO₂R(2) or a suitable hydroxylprotecting group, with an oxophilic electrophilic reagent in a mannerthat is effective to provide the oxazoline, wherein R_(b) is hydrogen,—COR(3), —SO₂R(2) or a suitable hydroxyl protecting group and R_(c) isH, —COR(3) or —SO₂R(2); wherein R(1), R(2) and R(3) independentlyrepresent a substituted or unsubstituted alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl group. Advantageously, the methods ofthis invention provide nelfinavir mesylate and its free base inrelatively high yield and employ fewer synthetic steps than the priorart methods.

[0010] This invention also relates to methods for making intermediatecompounds that are useful in the method of preparation of nelfinavirmesylate and its free base. In addition, this invention relates tomethods for the preparation of chiral starting materials that are usefulin the methods for the preparation of nelfinavir mesylate and its freebase according to this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0011] This invention provides novel and useful methods for theconversion of amino-tetrahydrofuran derivatives to oxazolineintermediates that are useful in the preparation of nelfinavir mesylateand nelfinavir free base. All compounds of the inventive methods of thisinvention that contain at least one chiral center may exist as singlestereoisomers, racemates and/or mixtures of enantiomers and/ordiastereomers unless otherwise indicated. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthis invention. Moreover, the scope of this invention is not intended tobe limited to reactions of selected isomers. Although the reactionschemes described herein may be illustrated using compounds depicted asa single enantiomer or diastereomer, the methods of this invention areintended to encompass reactions of any isomer or racemic mixture ofthese compounds.

[0012] When used to describe a particular compound, the term “chiral” isused herein to indicate that the compound is substantiallyenantiomerically and/or diastereomerically pure, for example, as in theterm “chiral amino-tetrahydrofuran.” Compounds that are substantiallyenatiomerically pure contain at least 90% of a single isomer andpreferably contain at least 95% of a single isomer. More preferably, thechiral compounds in this invention contain at least 97.5% of a singleisomer and most preferably contain at least 99% of a single isomer.Compounds identified herein as single stereoisomers are meant todescribe compounds that are present in a form that contains at least 90%of a single isomer. The term “racemic” or “racemic mixture” refers to amixture of equal amounts of enantiomeric compounds, which encompassesmixtures of enantiomers and/or mixtures of enantiomeric diastereomers.

[0013] The method of this invention provides for the conversion of anamino-tetrahydrofuran, I, to an oxazoline, II, as illustrated below:

[0014] wherein

[0015] R_(a) is hydrogen or —COR(1)

[0016] R_(b) is hydrogen, —COR(3), —SO₂R(2) or a suitable hydroxylprotecting group;

[0017] R_(c) is hydrogen, —COR(3) or —SO₂R(2);

[0018] wherein R(1), R(2) and R(3) independently represent a substitutedor unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroarylgroup.

[0019] As used herein, the term “alkyl” represents a straight orbranched chain alkyl group, preferably having one to eight, morepreferably having one to six, and most preferably having from one tofour carbon atoms. The term “C₁-C₆ alkyl” represents a straight orbranched alkyl chain having from one to six carbon atoms. ExemplaryC₁-C₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, andthe like. The term “C₁-C₆ alkyl” includes within its definition the term“C₁-C₄ alkyl.”

[0020] The term “cycloalkyl” represents a group comprising a saturatedor partially unsaturated, mono- or poly-carbocyclic ring, preferablyhaving 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclicrings having from 3-7, preferably 3-6, carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl and the like. An exemplary cycloalkyl is aC₅-C₇ cycloalkyl, which is a hydrocarbon ring structure containing fromfive to seven carbon atoms.

[0021] The term “aryl” represents a group comprising an aromatic,monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10,14, or 18 carbon ring atoms, to which may be fused one or morecycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups whichmay be unsubstituted or substituted by one or more of the substituentsdescribed below Illustrative examples of aryl groups include, but arenot limited to, phenyl, napthyl, anthryl, phenanthryl, fluoren-2-yl,indan-5-yl, and the like.

[0022] The term “heterocycloalkyl” represents a group comprising anon-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical,which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or 18 ring atoms and which includes 1, 2, 3,4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, and towhich may be fused one or more cycloalkyl groups, aryl groups, orheteroaryl groups which may be unsubstituted or substituted by one oremore of the substituents described below. Illustrative examples ofheterocycloalkyl groups include, but are not limited to azetidinyl,pyrrolidyl, piperidyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl,tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl,azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.

[0023] The term “heteroaryl” represents a group comprising an aromaticmonovalent monocyclic, bicyclic, or tricyclic radical, containing 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1,2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, towhich may be fused one or more cycloalkyl groups, heterocycloalkylgroups, or aryl groups, which may be unsubstituted or substituted by oneor more of the substituents described below. Illustrative examples ofheteroaryl groups include, but are not limited to, thienyl, pyrrolyl,imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl,thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl.

[0024] In this invention, each of the above alkyl, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl groups may be substituted by one or moresubstituents. If the substituents themselves are not compatible with themethods of this invention, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions usedin these methods. The protecting group may be removed at a suitablepoint in the reaction sequence of the method to provide a desiredintermediate or target compound. Suitable protecting groups and themethods for protecting and de-protecting different substituents usingsuch suitable protecting groups are well known to those skilled in theart; examples of which may be found in T. Green & P. Wuts, ProtectiveGroups in Organic Synthesis (2nd Ed. 1991), which is incorporated hereinby reference in its entirety. In some instances, a substituent may bespecifically selected to be reactive under the reaction conditions usedin the methods of this invention. Under these circumstances, thereaction conditions convert the selected substituent into anothersubstituent that is either useful in an intermediate compound in themethods of this invention or is a desired substituent in a targetcompound.

[0025] Exemplary substituents that may be present on an alkyl groupinclude aryl, cycloalkyl, beterocycloalkyl, heteroaryl, nitro (NO₂),amino, alkylamino, dialkylamino, carbamoyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, dialkylamino, alkoxy, aryloxy,halogen, hydroxyl, alkanoyl, acyloxy, aroyl, aroyloxy, carboxyl,alkoxycarbonyl, aryloxycarbonyl, alkylcarbonylamino, arylcarbonylamino,mercapto, alkylthio, arylthio, wherein any of the aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted by one or more of alkyl, aryl, nitro (NO₂),amino, halogen, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio orarylthio. Exemplary substituents that may be present on the above aryl,cycloalkyl, heterocycloalkyl or heteroaryl groups include alkyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, nitro (NO₂), amino,alkylamino, dialkylamino, carbamoyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, dialkylamino, alkoxy, aryloxy,halogen, hydroxyl, alkanoyl, acyloxy, aroyl, aroyloxy, carboxyl,alkoxycarbonyl, aryloxycarbonyl, alkylcarbonylamino, arylcarbonylamino,mercapto, alkylthio, arylthio, wherein any of the alkyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the abovesubstituents may be further substituted by one or more of alkyl, aryl,nitro (NO₂), amino, halogen, hydroxyl, alkoxy, aryloxy, mercapto,alkylthio or arylthio.

[0026] The terms “halogen” and “halo” represent chloro, fluoro, bromo oriodo substituents.

[0027] Exemplary substituted alkyls include halo(C₁-C₄)alkyl, whichrepresents a straight or branched alkyl chain having from one to fourcarbon atoms with 1-3 halogen atoms attached to it. Exemplaryhalo(C₁-C₄)alkyl groups include chloromethyl, 2-bromoethyl,1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl,iodo-t-butyl, trifluoromethyl, and the like. Another exemplarysubstituted alkyl is hydroxy (C₁-C₄)alkyl, which represents a straightor branched alkyl chain having from one to four carbon atoms with ahydroxy group attached to it. Exemplary hydroxy(C₁-C₄)alkyl groupsinclude hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxyisopropyl, 4-hydroxybutyl, and the like. Yet another exemplarysubstituted alkyl is C₁-C₄ alkylthio(C₁-C₄)alkyl, which is a straight orbranched C₁-C₄ alkyl group with a C₁-C₄ alkylthio group attached to it.Exemplary C₁-C₄ alkylthio(C₁-C₄)alkyl groups include methylthiomethyl,ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.Another exemplary substituted alkyl is heterocycloalkyl(C₁-C₄)alkyl orheteroaryl(C₁-C₄)alkyl, which is a straight or branched alkyl chainhaving from one to four carbon atoms to which is attached aheterocycloalkyl or heteroaryl group. Exemplaryheterocycloalkyl(C₁-C₄)alkyl and heteroaryl(C₁-C₄)alkyl groups includepyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl,3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and thelike. Yet another exemplary substituted alkyl is aryl(C₁-C₄)alkyl, whichis a straight or branched alkyl chain having from one to four carbonatoms with an aryl group attached to it. Exemplary aryl(C₁-C₄)alkylgroups include phenylmethyl (benzyl), 2-phenylethyl, 3-naphthyl-propyl,1-naphthylisopropyl, 4-phenylbutyl and the like.

[0028] Exemplary substituted aryls include a phenyl or naphthyl ringsubstituted with one or more substituents, preferably one to threesubstituents, independently selected from halogen, hydroxyl,morpholino(C₁-C₄)alkoxycarbonyl, pyridyl (C₁-C₄)alkoxycarbonyl,halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄alkoxycarbonyl, carbamoyl, N-(C₁-C₄)alkylaminocarbonyl, amino,C₁-C₄alkylamino, di(C₁-C₄)alkylamino or a group of the formula—(CH₂)_(a)—R₇ where a is 1, 2, 3 or 4 and R₇ is hydroxy, C₁-C₄ alkoxy,carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino ordi(C₁-C₄)alkylamino.

[0029] Exemplary substituted heterocycloalkyls and heteroaryls may besubstituted with 1,2 or 3 substituents independently selected fromhalogen, halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄alkoxycarbonyl, carbamoyl, N-(C₁-C₄)alkylcarbamoylN-(C₁-C₄)alkylaminocarbonyl, amino, C₁-C₄alkylamino, di(C₁-C₄)alkylaminoor a group having the structure —(CH₂)_(a)—R₇ where a is 1, 2, 3 or 4and R₇ is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino,carbamoyl, C₁-C₄alkylamino or di(C₁-C₄)alkylamino.

[0030] Examples of substituted heterocycloalkyls include, but are notlimited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples ofsubstituted heteroaryls include, but are not limited to,3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl,4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl,3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl,4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl,2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl,2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.

[0031] In general terms, the conversion of a tetrahydrofuran, I, to anoxazoline, II, may be conducted by treatment of the tetrahydrofuran,wherein R_(a) is —COR(1) and R_(b) is hydrogen, —COR(3), —SO₂R(2) or asuitable hydroxyl protecting group, with an oxophilic electrophilicreagent that facilitates tetrahydrofuran ring-opening to provide theoxazoline, wherein R_(b) is hydrogen, —COR(3), —SO₂R(2) or a suitablehydroxyl protecting group and R_(c) is hydrogen, —COR(3) or —SO₂R(2).Accordingly, the hydroxyl protecting groups that may be suitable for usein the method of this invention (as R_(b)) include those hydroxylprotecting groups that are stable to the oxophilic electrophilicreagents or reagent combinations described herein. Suitable protectinggroups and the methods for protecting and de-protecting hydroxylsubstituents using such suitable protecting groups are well known tothose skilled in the art; examples of which may be found in T. Green &P. Wuts, supra.

[0032] Typically, the first step in the method of this inventioncomprises the formation of the chiral tetrahydrofuran amide, B, from theknown amino-tetrahydrofuran, A, using any suitable, conventionalprocedure. Examples of such conventional procedures may be found in T.Green & P. Wuts, supra, and include treatment with a suitable acidhalide, R(1)COX, in the presence of a base, where X is a halogen,treatment with a suitable acid, R(1)COOH, in the presence of a suitablecoupling reagent, e.g. dicyclohexylcarbodiimide, and the like.Preferably, this reaction is conducted using an acid chloride in thepresence of triethylamine base.

[0033] In one embodiment of this invention, the hydroxyl moiety of thechiral tetrahydrofuran amide, B, may be substituted by R_(b), whereR_(b) is —SO₂R(2) or a suitable protecting group, as defined above.Preferably, the hydroxyl moiety is converted to an alkyl orarylsulfonate (—SO₂R(2)), more preferably, a mesylate or tosylate. Themethods for forming such —OSO₂R(2) groups are well know in the art andmay be accomplished using any suitable conventional procedure. Examplesof such conventional procedures may also be found in T. Green & P. Wuts,supra. Preferably, this reaction is conducted using methanesulfonylchloride or p-toluenesulfonyl chloride in the presence of triethylaminebase.

[0034] This hydroxy-substituted, chiral tetrahydrofuran amide, C, maythen be converted to a chiral oxazoline, D. This conversion may beconducted using an oxophilic electrophilic reagent that facilitatestetrahydrofuran ring-opening and oxazoline ring-formation. As usedherein the term “oxophilic electrophilic reagent” refers to a singlereagent, or a set of reagents which when combined generate an oxophilicelectrophilic intermediate, which facilitates tetrahydrofuranring-opening and oxazoline ring-formation. Examples of oxophilicelectrophilic reagents include, but are not limited to, suitableoxophilic Lewis acids (for example, metal halide Lewis acids, such astitanium tetrachloride, or strong oxophilic protic acids, such astrifluoromethanesulfonic acid (triflic acid)), a suitable acidanhydride, a combination of a suitable acid anhydride or a suitable acidhalide with a suitable Lewis acid. Suitable anhydrides and acid halidesinclude the anhydrides and acid halides (e.g., acid chlorides) of anyconventional alkyl or aryl carboxylic or sulfonic acid as well asanhydrides of strong acids, for example, triflic anhydride. SuitableLewis acids include well-known metal halide Lewis acids, such astitanium tetrachloride, aluminum trichloride and the like, and strongprotic acids, such as sulfuric acid, nitric acid, phosphoric acid,trifluoroacetic acid, trifluoromethanesulfonic acid and the like.Generally, the reaction of the tetrahydrofuran-amide with an oxophilicelectrophilic reagent to form the oxazoline may be conducted at atemperature of between —40° C. and 70° C. in aprotic solvents,including, but not limited to ethyl acetate, isopropyl acetate,dichloromethane, benzene and toluene, using about 1 to about 20 molarequivalents of the oxophilic electrophilic reagent (relative to thetetrahydrofuran-amide).

[0035] In the course of this reaction, the primary hydroxyl moietyformed on opening of the tetrahydrofuran may become substituted with the“cationic”moiety of the acid used in the reaction. When employing aLewis acid or a strong protic acid as the oxophilic electrophilicreagent, the resulting oxazoline contains an unsubstituted primaryhydroxyl moiety (where R_(c) is H) either because the “cationic moiety”of the acid is H⁺ or because the rapid hydrolysis of any intermediateformed using such reagents generates this product. The resultinghydroxyl moiety may be converted to into any art-recognized derivativeusing conventional techniques (e.g., an ether via alkylation, an estervia acylation, a carbonate by treatment with an alkyl- oraryl-oxycarbonyl chloride, or equivalent thereof, a carbamate bytreatment with an isocyante, etc.).

[0036] For the preparation of nelfinavir and nelfinavir mesylate, thetetrahydrofuran amide is preferably converted to an oxazoline-esterderivative by treatment with an oxophilic electrophilic reagentcomprising a suitable anhydride, for example, triflic anhydride, or witha combination of an anhydride or acid halide with a Lewis acid. Suchreagents are capable of generating acylium ion intermediates and arewell known in the art. For example, a suitable acylium intermediate maybe prepared in situ by treatment of a suitable acid anhydride,optionally with a suitable protic acid, or by treatment of a suitableacid halide with a suitable Lewis acid. Suitable acid anhydrides, acidhalides and Lewis acids are as described hereinabove. In the course ofthe reaction employing these reagents, the primary hydroxyl moietyformed on opening of the tetrahydrofuran becomes substituted with thealkyl or aryl carboxyl moiety of the anhydride or acid halide(illustrated as R_(c) above, where R_(c) is —COR(3), as defined above)used in the reaction. As exemplified herein, a useful oxophilicelectrophilic reagent combination is comprised of acetic anhydride andsulfuric acid. Accordingly, in this embodiment of the method of thisinvention, the resulting oxazoline contains an acetylated primaryhydroxyl moiety.

[0037] Generally, conversion of the tetrahydrofuran-amide to theoxazoline may be accomplished using an excess molar equivalent amount ofeach reagent of an oxophilic electrophilic reagent combination. Thisreaction may be conducted at a temperature of between −40° C. and 70° C.in aprotic solvents, including, but not limited to ethyl acetate,isopropyl acetate, dichloromethane, benzene and toluene, using about 1to about 20 molar equivalents of a suitable acid and about 1 to about 20molar equivalents of a suitable anhydride (relative to thetetrahydrofuran-amide) and using the acid anhydride and acid in arelative molar ratio of from about 1:5 to about 5:1 (anhydride:acid).Preferably, the conversion may be accomplished using an excess molarequivalent amount of the oxophilic electrophilic reagent, i.e., at least2 to about 20 molar equivalents of the oxophilic electrophilic reagent.More preferably, the reaction may be conducted using about 2 to about 20molar equivalents of acid and about 2 to about 20 molar equivalents of asuitable anhydride, wherein the ratio of anhydride to acid is from about1:1 to about 5:1. For example, as exemplified herein, the conversion maybe accomplished using 7.5 equivalents of a strong acid and 15equivalents of an acid anhydride (i.e., wherein the ratio of anhydrideto acid is 2:1 (in the range of from about 1.5:1 to about 3:1).

[0038] As described in PCT/JP96/02756 (WO97/11937), the disclosure ofwhich is incorporated by reference herein, the resulting oxazoline, D,may be used for the preparation of intermediates, useful in thepreparation of nelfinavir, especially Compounds 20 and 19,

[0039] where R(4) is a substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl, or heteroaryl group and R(5) is asubstituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-arylgroup, wherein each alkyl or aryl moiety may be unsubstituted orsubstituted with the substituents described above.

[0040] In another embodiment of the method of this invention, thetetrahydrofuran-amide, B, may be directly converted to oxazoline, E. Theamide may be treated in a manner similar to that described above. Forexample, the tetrahydrofuran-amide, B, may be treated directly with asuitable acid anhydride in the presence of a suitable acid, such as, forexample, acetic anhydride and sulfuric acid, to form an oxazolinediester, E. Each hydroxyl moiety of the resulting oxazoline becomessubstituted with the alkyl or aryl carboxyl moiety (illustrated as—COR(3), where R(3) is as defined above) of the anhydride used in thereaction. Accordingly, if acetic anhydride is used in this method, bothhydroxyl moieties of the resulting oxazoline will be acetylated.

[0041] Each of the alkyl or aryl carboxyl moieties of oxazoline diester,E, may be removed (hydrolyzed to the corresponding hydroxyl moieties)using conventional procedures, for example, by treatment with a suitablebase in a suitable solvent, to form the oxazoline diol, F. Bases thatare suitable for effecting this hydrolysis are well known in the art andinclude potassium carbonate, sodium hydroxide, potassium hydroxide, andthe like. Solvents that are suitable for this hydrolysis are similarlywell known in the art and include, but are not limited to, loweralkanols (methanol, ethanol, isopropanol, etc.). Examples of otherconventional procedures for the hydrolysis of esters may be found in T.Green & P. Wuts, supra.

[0042] Conversion of the oxazoline diol, F, to nelfinavir via compound19 may be conducted in a manner similar to that described inPCT/JP96/02757 (WO97/11938) for the conversion of 2(R),3-dihydroxy-1(R)-phenylsulfanylmethyl-propyl)-carbamic acid benzyl esterto nelfinavir mesylate and its free base. The disclosure ofPCT/JP96/02757 (WO97/11938) is incorporated by reference herein. Forexample, selective functionalization of the primary and secondaryhydroxyl moieties of oxazoline diol, F, may be accomplished by firstselectively protecting the primary hydroxyl moiety using a suitablehydroxyl protecting group. Suitable hydroxyl protecting groups and themethods for protecting and de-protecting hydroxyl substituents usingsuch suitable protecting groups are well known to those skilled in theart; examples of which may be found in T. Green & P. Wuts, supra.Preferably, the primary hydroxyl moiety is protected as apara-nitrobenzoate ester. The secondary hydroxyl moiety may thereafterbe functionalized by conversion to a leaving group. The term “leavinggroup” as used herein refers to any group that departs from a moleculein a substitution reaction by breakage of a bond. Examples of leavinggroups include, but are not limited to, substituted or unsubstitutedarylsulfonates and alkylsulfonates, prepared using a substituted orunsubstituted aryl or alkylsulfonyl halide. Preferably, the hydroxylmoiety is converted to a mesylate. This sulfonylated-protected oxazolinemay then be converted to Compound 20 by addition of3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ), asdescribed in PCT/JP96/02757.

[0043] In a preferred embodiment of the method of this invention, R(1)is

[0044] where the R_(P) is a suitable phenolic hydroxyl protecting group,examples of which may be found in T. Green and P. Wuts, supra. In a morepreferred embodiment of this invention, R(1) is

[0045] wherein the acetyl moiety used to protect the phenolic hydroxylmoiety is reactive to the hydrolysis conditions used to convert E to F.Accordingly, in this embodiment of the invention, oxazoline F is atriol, wherein R(1) is

[0046] Selective functionalization of the phenolic, primary andsecondary hydroxyl moieties of the oxazoline triol, may be accomplishedby first selectively protecting the phenolic hydroxyl moiety using asuitable hydroxyl protecting group. Preferably, the phenolic hydroxylmoiety is protected as a para-nitrobenzoate ester. The primary hydroxylmoiety may then be protected using the same or different protectinggroup. If the same protecting groups is used, the phenolic and primaryhydroxyl moieties may be protected in a single step. The secondaryhydroxyl moiety may thereafter be functionalized by conversion to amesylate. This sulfonylated-di-protected oxazoline may then be convertedto Compound 20 by addition of3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ), in amanner similar to that described in PCT/JP96/02757.

[0047] This invention also provides a method for the preparation of achiral tetrahydrofuran amide, wherein the 4-hydroxyl moiety possessesstereochemistry opposite to that of the chiral tetrahydrofuran amide, B,described hereinabove. This method comprises conversion of thetetrahydrofiran amide, B, to a fused tetrahydrofuranyloxazoline, G, bytreatment with a substituted or unsubstituted sulfonylating reagentusing two equivalents of a base. This reaction may be conducted at atemperature of between −78° C. and 100° C. in suitable solvents,including, but not limited to ethyl acetate, isopropyl acetate, toluene,benzene, dichloromethane, tetrahydrofuran, and the like.

[0048] This fused heterocycle, G, may then be converted to chiraltetrahydrofuran amide, H, by treatment with aqueous acids, including,but not limited to, aqueous hydrochloric acid sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, and thelike. This reaction may be conducted at a temperature of between −40° C.and 100° C. in suitable solvents, including, but not limited to water,alcoholic solvents, or mixtures thereof, where suitable alcoholicsolvents include, but are not limited to lower alkanols, such asmethanol, isopropanol, ethanol, and the like.

[0049] The tetrahydrofuran-amide, H, may be converted to the oxazolinediester, J, by treatment with an acid anhydride and an acid, accordingthe methods described above. Hydrolysis of the alkyl or aryl carboxylmoieties of the oxazoline diester, J, to form diol, K, may also beaccomplished according to the methods described above.

[0050] The primary hydroxyl moiety of the resulting oxazoline diol, K,may be functionalized by conversion to a leaving group, by treatmentwith a substituted or unsubstituted aryl or alkylsulfonyl halide, asdescribed above. Preferably, the primary hydroxyl is converted to atosylate or mesylate. Treatment of this functionalized oxazoline with anucleophile, 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline(PHIQ) in the presence of a base, under conventional conditions,provides Compound 19. Conversion of Compound 19 into nelfinavir may beaccomplished in a manner similar to that described in PCT/JP96/02757.

[0051] In another embodiment of this invention, thetetrahydrofuran-amide, H,

[0052] may be converted to a protected tetrahydrofuran-amide, L, whereR(10) may be any suitable hydroxyl protecting group.

[0053] The protected tetrahydrofuran-amide, L, may then be converteddirectly to a protected oxazoline, M, by treatment with an oxophilicLewis acid, an oxophilic protic acid, or triflic anhydride, whereinR(10) is any suitable protecting group for a hydroxyl moiety and R(11)is H or substituted alkyl sulfonyl.

[0054] Conversion of the protected oxazoline, M, to nelfinavir may beconducted in a manner similar to that described hereinabove.

[0055] This invention further provides a method for the preparation ofthe chiral amino-tetrahydrofuran, A, or a salt thereof,

[0056] comprising treating the achiral fused epoxy-tetrahydrofuran, N,

[0057] with an amine reagent to form Compounds O or P, or a mixturethereof. This reaction may be conducted at a temperature of between −50°C. and 100° C. in suitable solvents, including, but not limited toalcoholic solvents, such as methanol, isopropanol, ethanol, and the likeor aprotic solvents, such as isopropyl acetate, ethyl acetate,tetrahydrofuran, and the like.

[0058] The amine reagent used in this method may be a chiral or anachiral aminating reagent. If the aminating reagent is chiral (i.e.,R(6) is a chiral moiety), the mixture of amino-tetrahydrofurans formedis a diastereomeric mixture that may be treated using conventionaltechniques to provide separated amino-tetrahydrofuran diastereoisomers.After the isomers are separated, the chiral moiety of the chiralaminating reagent may be removed to provide each of the resolvedamino-tetrahydrofuran enantiomers, or salts thereof. For the purposes ofthis separation, substituent R(6) is a suitable nitrogen protectinggroup that possesses a chiral center that is substantiallyenantiomerically pure. Preferably, R(6) is composed of at least 97.5% ofa single isomer and more preferably, is composed of at least 99% of asingle isomer. Moreover, the R(6) nitrogen protecting group must beremovable under conditions that do not racemize the chiralamino-tetrahydrofuran, 1. Preferably, R(6) is a substantiallyenantiomerically pure substituted or unsubstituted alkanoyl, aroyl,arylalkylcarbonyl, arylalkyl or heteroarylalkyl, wherein the alkyl, arylor heteroaryl moieties may be substituted with any of the alkyl, aryl orheteroaryl moieties described above. Most preferably, R(6) is

[0059] If the aminating reagent is achiral, for example, ammonia, themixture of amino-tetrahydrofurans formed is an enantiomeric mixture thatmay be treated with a chiral reagent in a manner effective to provide adiastereomeric mixture of amino-tetrahydrofurans, wherein the chiralreagent contains a chiral auxiliary substituent. This diastereomericmixture may be treated using conventional techniques to provideseparated amino-tetrahydrofuran diastereoisomers. After the isomers areseparated, the chiral auxiliary substituent may be separated from eachof the separated amino-tetrahydrofurans to provide the resolvedamino-tetrahydrofuran enantiomers, or salts thereof.

[0060] Exemplary techniques useful for the separation of stereoisomersare described in Enantiomers, Racemates and Resolutions, J. Jacques, A.Collet, S. Wilen, Krieger Pub. Co., (1991) Malabar, Fla., the disclosureof which is incorporated herein by reference. Examples of suchseparation techniques include crystallization, chromatography, and thelike. Advantageously, the chiral amino-tetrahydrofuran prepared by thismethod is substantially enantiomerically pure, containing at least 90%of a single isomer and preferably containing at least 95% of a singleisomer. More preferably, the chiral amino-tetrahydrofuran prepared bythis method contains at least 97.5% of a single isomer and mostpreferably contains at least 99% of a single isomer.

[0061] Specifically, this invention provides a method for thepreparation of:

[0062] wherein R(1) is substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl or heteroaryl, as defined above.Preferably, R(1) is a substituted or unsubstituted phenyl, or asubstituted or unsubstituted C₁-C₆ alkyl. More preferably, R(1) is asubstituted phenyl or CF₃.

[0063] Most preferably, R(1) is

[0064] R(2) is a substituted or unsubstituted alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl. Preferably, R(2) is a substituted orunsubstituted alkyl or aryl. More preferably, R(2) is methyl, phenyl ortolyl. Most preferably, R(2) is methyl. R(3) is a substituted orunsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.Preferably, R(3) is a substituted or unsubstituted alkyl or aryl. Morepreferably, R(3) is methyl or phenyl. Most preferably, R(3) is methyl.

[0065] A preferred embodiment of this method comprises the steps of:

[0066] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,

[0067] in a manner that is effective to convert theamino-tetrahydrofuran, 1, or a salt thereof, to tetrahydrofuran-amide,2,

[0068] (2) treating tetrahydrofuran-amide, 2, in a manner that iseffective to convert the tetrahydrofuran-amide, 2, to tetrahydrofuranamide-sulfonate, 3,

[0069] comprising the step-wise treatment of tetrahydrofuran-amide, 2,with at least one molar equivalent amount of a sulfonylating reagent,followed by treatment with a base, wherein the molar equivalent amountof base used in the treatment is less than the molar equivalent amountof the sulfonylating reagent, and

[0070] (3) treating tetrahydrofuran amide-sulfonate, 3, in a manner thatis effective to convert the tetrahydrofuran amide-sulfonate, 3, to theoxazoline, 18.

[0071] Preferably, tetrahydrofuran-amide, 2, may be treated first with asubstituted or unsubstituted alkyl or aryl sulfonyl chloride, followedby treatment with less than a molar equivalent amount (with respect tothe amount of sulfonyl chloride) of a base, in a manner effective toconvert the tetrahydrofuran-amide, 2, to tetrahydrofuranamide-sulfonate, 3, and tetrahydrofuran amide-sulfonate, 3, may betreated with an oxophilic electrophilic reagent in a manner that iseffective to convert the tetrahydrofuran amide-sulfonate, 3, to theoxazoline, 18.

[0072] This invention also provides a method for the preparation ofCompound 19:

[0073] wherein R(4) is a substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl, or heteroaryl group and R(5) is asubstituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-arylgroup, wherein each alkyl or aryl moiety may be substituted orunsubstituted with the substituents described above. Most preferably,R(4) is

[0074] and R(5) is N-t-butyl.

[0075] This method is comprised of the following steps:

[0076] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,

[0077] in a manner that is effective to convert theamino-tetrahydrofuran, 1, or a salt thereof, to tetrahydrofuran-amide,2,

[0078] (2) treating tetrahydrofuran-amide, 2, in a manner that iseffective to convert the tetrahydrofuran-amide, 2 to tetrahydrofuranamide-sulfonate, 3,

[0079] comprising the step-wise treatment of tetrahydrofuran-amide, 2,with at least one molar equivalent amount of a sulfonylating reagent,followed by treatment with a base, wherein the molar equivalent amountof base used in the treatment is less than the molar equivalent amountof the sulfonylating reagent, and

[0080] (3) treating tetrahydrofuran amide-sulfonate, 3, in a manner thatis effective to convert the tetrahydrofuran amide-sulfonate, 3, to theoxazoline, 18,

[0081] (4) treating oxazoline, 18, in a manner that is effective toconvert the oxazoline, 18, to Compound 20,

[0082]  and

[0083] (5) treating Compound 20 in a manner that is effective to convertCompound 20 to Compound 19.

[0084] Preferably, tetrahydrofuran-amide, 2, may be treated first with asubstituted or unsubstituted alkyl or aryl sulfonyl chloride, followedby treatment with less than a molar equivalent amount (with respect tothe amount of sulfonyl chloride) of a base, in a manner effective toconvert the tetrahydrofuran-amide, 2, to tetrahydrofuranamide-sulfonate, 3, and tetrahydrofuran amide-sulfonate, 3, may betreated with an oxophilic electrophilic reagent in a manner that iseffective to convert the tetrahydrofuran amide-sulfonate, 3, to theoxazoline, 18; oxazoline 18 may be treated with3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner thatis effective to convert oxazoline 18 to Compound 20, which maybeconverted to Compound 19, according to the procedures described inPCT/JP96/02756 (WO97/11937).

[0085] Another method of this invention comprises the method for thepreparation of

[0086] comprising the steps of:

[0087] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,

[0088] in a manner that is effective to convert theamino-tetrahydrofuran, 1, or a salt thereof, to tetrahydrofuran-amide,2,

[0089] (2) treating tetrahydrofuran-amide, 2, in a manner that iseffective to convert the tetrahydrofuran-amide, 2, to oxazolinetriester, 4,

[0090] (3) treating oxazoline triester, 4, in a manner that is effectiveto convert the oxazoline triester, 4, to oxazoline triol, 5,

[0091] (4) treating oxazoline, 5, in a manner that is effective toconvert the oxazoline triol, 5, to Compound 6 or Compound 7,

[0092] (5) treating Compound 7 in a manner that is effective to convertCompound 7 to Compound 8,

[0093] (6) treating Compound 8 in a manner that is effective to convertCompound 8 to Compound 20;

[0094] wherein R(7) is any suitable protecting group for a hydroxylmoiety. Suitable hydroxyl protecting groups and the methods forprotecting and de-protecting hydroxyl substituents using such suitableprotecting groups are well known to those skilled in the art; examplesof which may be found in T. Green & P. Wuts, supra. Preferably, R(7) istrialkylsilyl, dialkyl-monoarylsilyl, diaryl-monoalkylsilyl, substitutedor unsubstituted aroyl or alkanoyl. Preferably, R(7) is trimethylsilyl,tert-butyldimethylsilyl, benzoyl, para-nitrobenzoyl, triisopropylsilyl,and the like. Most preferably, R(7) is a para-nitrobenzoyl (PNB) moiety.

[0095] Preferably, tetrahydrofuran-amide, 2, may be treated with anoxophilic electrophilic reagent in a manner that is effective to convertthe tetrahydrofuran-amide, 2, to oxazoline triester, 4. Oxazolinetriester, 4, may be hydrolyzed to oxazoline triol, 5. The phenolichydroxyl moiety of oxazoline triol, 5, may be protected with a suitablehydroxyl protecting group, in a manner that is effective to convert theoxazoline triol, 5, to protected oxazoline, 6. Alternatively, both thephenolic and primary hydroxyl moieties of oxazoline triol, 5, may beprotected with a suitable hydroxyl protecting group, in a manner that iseffective to convert the oxazoline triol, 5, to di-protected oxazoline,7. Di-protected oxazoline, 7, may be treated with a substituted orunsubstituted alkyl or aryl sulfonylating reagent, in a manner that iseffective to convert the oxazoline, 7, to a sulfonylated-di-protectedoxazoline, 8. The sulfonylated-di-protected oxazoline, 8, may be treatedwith 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a mannerthat is effective to convert the oxazoline, 8, to Compound 20.

[0096] Yet another method according to this invention comprises a methodfor the preparation of Compound 19:

[0097] This method comprises the steps of:

[0098] (1) converting amino-tetrahydrofuran, 1,

[0099] or a salt thereof to tetrahydrofuran-amide, 2,

[0100] (2) converting tetrahydrofuran-amide, 2, to oxazoline triester,4,

[0101] (3) converting oxazoline triester, 4 to oxazoline triol 5,

[0102] (4) converting oxazoline triol, 5 to di-protected oxazoline, 7;

[0103] wherein the di-protected oxazoline, 7, may be converted tonelfinavir via Compound 19 using the method described in PCT/JP96/02757.

[0104] For example, the di-protected oxazoline, 7, may be converted toCompound 19 by the method comprising the steps of:

[0105] (1) converting di-protected oxazoline, 7, tosulfonylated-di-protected oxazoline, 8,

[0106] (2) converting the sulfonylated-di-protected oxazoline, 8, toCompound 20,

[0107] and

[0108] (3) converting Compound 20 to Compound 19.

[0109] Preferably, tetrahydrofuran-amide, 2, may be treated with anoxophilic electrophilic reagent in a manner that is effective to convertthe tetrahydrofuran-amide, 2, to oxazoline triester, 4. Oxazolinetriester, 4, may be hydrolyzed to oxazoline triol, 5. The phenolic andprimary hydroxyl moieties of oxazoline triol, 5, may be protected with asuitable hydroxyl protecting group, in a manner that is effective toconvert the oxazoline triol, 5, to di-protected oxazoline, 7. Thedi-protected oxazoline, 7, may be treated with a substituted orunsubstituted alkyl or aryl sulfonylating reagent, in a manner that iseffective to convert the oxazoline, 7, to a sulfonylated-di-protectedoxazoline, 8. The sulfonylated-di-protected oxazoline, 8, may be treatedwith 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a mannerthat is effective to convert the oxazoline, 8, to Compound 20.

[0110] Still another method according to this invention relates to amethod for the preparation of Compound 19:

[0111] wherein the method comprises the steps of:

[0112] (1) converting amino-tetrahydrofuran, 1, or a salt thereof totetrahydrofuran-amide, 2,

[0113] (2) converting tetrahydrofuran-amide, 2, to fusedtetrahydrofuranyloxazoline, 9,

[0114] (3) converting the fused tetrahydrofuranyloxazoline, 9, totetrahydrofuran-amide, 10,

[0115] (4) converting the tetrahydrofuran-amide, 10, to an oxazolinetriester, 11,

[0116] (5) converting the oxazoline triester, 11, to oxazoline triol,12,

[0117] (6) converting the oxazoline triol, 12, to a functionalizedoxazoline, 13,

[0118] wherein R(8) together with the oxygen to which it is attachedforms a suitable leaving group and R(9) is H or R(8),

[0119] (7) converting the functionalized oxazoline, 13, to Compound 20,

[0120] (8) converting Compound 20 to Compound 19,

[0121] Preferably, tetrahydrofuran-amide, 2, may be treated with asubstituted or unsubstituted alkyl or aryl sulfonylating reagent, in amanner effective to convert the tetrahydrofuran-amide, 2, to fusedtetrahydrofuranyloxazoline, 9. The fused tetrahydrofuranyloxazoline, 9,may be hydrolyzed to tetrahydrofuran-amide, 10. Tetrahydrofuran-amide,10, may be treated with an oxophilic electrophilic reagent in a mannerthat is effective to convert the tetrahydrofuran-amide, 10, to oxazolinetriester, 11. Oxazoline triester, 11, may be hydrolyzed to oxazolinetriol, 12. Oxazoline triol, 12, may be functionalized by treatment witha substituted or unsubstituted alkyl or aryl sulfonylating reagent in amanner effective to convert oxazoline, 12, to a functionalizedsulfonylated oxazoline, 13. Oxazoline, 13, may be treated with3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner thatis effective to convert the oxazoline to Compound 20.

[0122] Another method of this invention comprises the method for thepreparation of Compound 20:

[0123] comprising the steps of:

[0124] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,

[0125] in a manner that is effective to convert theamino-tetrahydrofuran, 1, or a salt thereof, totetrahydrofuran-hydroxy-amide, 10,

[0126] (2) treating tetrahydrofuran-hydroxy-amide, 10, in a manner thatis effective to protect the hydroxyl moiety of thetetrahydrofuran-amide, 10, to form a protected tetrahydrofuran-amide,21,

[0127] (3) treating the protected tetrahydrofuran-amide, 21, in a mannerthat is effective to convert the tetrahydrofuran-amide, 21, to aprotected oxazoline, 22,

[0128] (4) treating protected oxazoline, 22, in a manner that iseffective to convert the oxazoline, 22, to Compound 20;

[0129] wherein R(10) is any suitable protecting group for a hydroxylmoiety and R(11) is H or substituted alkyl sulfonyl.

[0130] Suitable R(10) hydroxyl protecting groups and the methods forprotecting and de-protecting hydroxyl substituents using such suitableprotecting groups are well known to those skilled in the art; examplesof which may be found in T. Green & P. Wuts, supra.

[0131] Preferably, the hydroxyl moiety of tetrahydrofuran-amide, 10, maybe protected with a suitable hydroxyl protecting group, in a manner thatis effective to convert the tetrahydrofuran-amide, 10, to a protectedtetrahydrofuran-amide, 21, where R(10) is any suitable protecting group.The protected tetrahydrofuran-amide, 21, may be treated with anoxophilic electrophilic reagent in a manner that is effective to convertthe protected tetrahydrofuran-amide, 21, to a protected oxazoline, 22.Preferably, the tetrahydrofuran-amide, 21, is treated with an oxophilicLewis acid, an oxophilic protic acid, or triflic anhydride.

[0132] Another method of the invention relates to a method for preparinga chiral amino-tetrahydrofuran, 1, or a salt thereof in substantiallydiastereomerically pure form.

[0133] The method comprises the steps of: (1) converting fusedepoxy-tetrahydrofuran, 14,

[0134] to a stereoisomeric mixture of amino-tetrahydrofurans,

[0135] (2) treating the stereoisomeric mixture of amino-tetrahydrofuransin a manner effective to resolve the amino-tetrahydrofuranstereoisomers, and

[0136] (3) isolating the resolved stereoisomers ofamino-tetrahydrofuran, 1 and 1′, or a salt thereof

[0137] The epoxy-tetrahydrofuran, 14, may be treated with an aminatingreagent to form the stereoisomeric mixture of amino-tetrahydrofurans, 1and 1′.

[0138] As described herein, the compounds of this invention may be usedas salts. The salts may be pharmaceutically acceptable salts. The term“pharmaceutically acceptable salt” refers to those salts that retain thebiological effectiveness and properties of the free acids and basesand/or that are not biologically or otherwise undesirable.

[0139] Examples of pharmaceutically acceptable salts include, but arenot limited to, sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,nitrobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, sulfonates, phenylsulfonates, toluenesulfonates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, hydroxybutyrates, glycolates,tartrates and mandelates. Although any pharmaceutically acceptable saltof the compounds described hereinabove may be prepared, preferred saltsare p-toluenesulfonate salts.

[0140] If a compound of an inventive method of this invention is a base,the desired salt may be prepared by any suitable method known to theart, including treatment of the free base with an acid. Such treatmentprovides the salt as a protonated base, together with a counterion,which may include, but is not limited to, inorganic ions, such ashalogens, pseudohalogens, sulfates, hydrogen sulfates, nitrates,hydroxides, phosphates, hydrogen phosphates, dihydrogen phosphates,perchlorates, and related complex inorganic anions, and organic ions,such as carboxylates, sulfonates, bicarbonates and carbonates. Exemplaryacids useful in the method of this invention include inorganic acids,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids, such as acetic acid,maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid,pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidylacids such as glucuronic acid and galacturonic acid, alpha-hydroxy acidssuch as citric acid and tartaric acid, amino acids such as aspartic acidand glutamic acid, aromatic acids such as benzoic acid and cinnamicacid, sulfonic acids such as p-toluenesulfonic acid, phenylsulfonic acidor methanesulfonic acid, or the like.

[0141] If a compound of an inventive method of this invention is anacid, the desired salt may be prepared by any suitable method known tothe art, including treatment of the free acid with an inorganic ororganic base, such as an amine (primary, secondary or tertiary), or analkali metal or alkaline earth metal hydroxide or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids such as glycine and arginine, ammonia, primary, secondary andtertiary amines, cyclic amines such as piperidine, morpholine andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0142] This invention also provides novel and useful methods forproducing intermediates that are especially useful in the preparation ofnelfinavir mesylate and nelfinavir free base.

[0143] Particularly useful intermediates are Compounds 19′ and 20′. Asillustrated below, these compounds may be prepared from chiraltetrahydrofuran Compounds 1′ or 2′.

[0144] Compound 18′ may be prepared by the reaction sequence illustratedin Scheme I, below. In this embodiment of the method of this invention,chiral amino-tetrahydrofuran, 1′, is treated with3-acetoxy-2-methylbenzoyl chloride (AMBC) under conditions effective toform an amide, (12-acetoxy-3-methyl benzamide, 2′) or a salt thereof.The resulting amide, tetrahydrofuran-amide, 2′, may be treated withmethanesulfonyl chloride in the presence of a base, such as, forexample, triethylamine, under conditions effective to derivatize thesecondary alcohol of tetrahydrofuran-amide, 2′, providing anintermediate mesylate tetrahydrofuran amide-sulfonate, 3′, which neednot be isolated. For example, this reaction may be conducted by firsttreating tetrahydrofuran 2′ with at least one molar equivalent ofmethanesulfonyl chloride, followed by addition of less than a molarequivalent amount (with respect to the amount of methanesulfonylchloride) of triethylamine. Tetrahydrofuran amide-sulfonate, 3′, maythen be treated with an anhydride, such as, for example, aceticanhydride, and a strong acid, such as, for example, sulfuric acid, underconditions effective to produce Compound 18′. For example,tetrahydrofuran amide-sulfonate, 3′, may be treated with 15 molarequivalents of acetic anhydride and 7.5 molar equivalents of a strongacid, such as, for example, sulfuric acid, to produce Compound 18′.Other strong acids useful in this treatment step includetrifluoromethanesulfonic acid, nitric acid, phosphoric acid, and thelike.

[0145] It is considered within the ordinary skill of one in the artthrough routine experimentation to determine the reaction conditions(solvent, reaction time, temperature, etc.) that are effective toproduce all of the compounds, described herein. For example, theabove-described reactions for the conversion of amino-tetrahydrofuran,1′, to Compound 19′, using the moisture-sensitive acid chloride, AMBC,and sulfonyl chloride, mesylchloride, would preferably be conducted inan aprotic solvent (i.e., one that is not water or an alcohol).Preferably, the aprotic solvent is an aprotic solvent, e.g. ethylacetate, isopropyl acetate, toluene, benzene and the like.

[0146] The preparation of Compound 20′, as illustrated in the reactionsequence of Scheme II, below, may also be prepared from theamino-tetrahydrofuran, 1′, or a pharmaceutically acceptable saltthereof. As in the above-described reaction sequence, the first step ofthis sequence involves the formation of the amide intermediate,tetrahydrofuran-amide, 2′. This amide intermediate may be treateddirectly with an anhydride, such as, for example, acetic anhydride, anda strong acid, such as, for example, sulfuric acid, to form oxazolinetriester, 4′. Each of the acetoxy moieties of oxazoline triester, 4′,may be removed (hydrolyzed to the corresponding hydroxyl moieties), bytreatment with a suitable base in a suitable solvent, to form theoxazoline triol, 5′. Bases that are suitable for effecting thishydrolysis are known in the art and include potassium carbonate, sodiumhydroxide, potassium hydroxide, and the like. Solvents that are suitablefor effecting this hydrolysis are similarly known in the art and includelower alkanols (methanol, ethanol, isopropanol, etc.).

[0147] Advantageously, the phenolic, primary and secondary hydroxylmoieties of oxazoline triol, 5′ may be selectively protected, asillustrated below. For example, the phenolic hydroxyl moiety may beprotected as the p-nitrobenzoate, Compound 6′, using p-nitrobenzoylchloride. The primary hydroxyl moiety of Compound 6′ may then beselectively protected using the same or a different protecting group.Alternatively, both the phenolic and primary hydroxyl moieties ofoxazoline triol, 5′, may be protected using p-nitrobenzoyl chloride toform the di-p-nitrobenzoate, Compound 7′. This process may be conductedin a single step, using two equivalents of p-nitrobenzoyl chloride, orin a stepwise process, as described above.

[0148] As illustrated in Scheme III, treating Compound 7′ withmethanesulfonyl chloride (although another substituted or unsubstitutedalkyl or aryl sulfonyl chloride may be used) in the presence of a base,such as, for example, triethylamine, provided Compound 8′, which may beconverted into Compound 20′ by addition of3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ) in thepresence of potassium carbonate and methanol. Further treatment withthiophenol provided nelfinavir. Treatment of Compound 7′ with thesulfonyl chloride and base may be conducted using conventionalconditions.

[0149] An alternative reaction sequence for preparing Compound 19′beginning with the formation of tetrahydrofuran-amide, 2′, fromamino-tetrahydrofuran, 1′, comprises the formation of the fusedtetrahydrofuranyloxazoline, 9′, as illustrated in Scheme IV, below.Treatment of the tetrahydrofuran-amide, 2′, with methanesulfonylchloride (although another substituted or unsubstituted alkyl or arylsulfonyl chloride may be used) in the presence of a base, such as, forexample, triethylamine, provides the novel fusedtetrahydrofuranyloxazoline, 9′. Acid treatment of this oxazolineprovides the tetrahydrofuran-amide, 10′, wherein the stereochemistry ofthe 4-hydroxyl moiety is opposite that of the starting tetrahydrofuran,2′. Treatment of the tetrahydrofuran-amide, 10′, with acetic anhydridein the presence of a strong acid, such as sulfuric or nitric acid,affords Compound 11′, a triacetate. Hydrolysis of this triacetateprovides triol, 12′.

[0150] As illustrated in Scheme V, treatment of triol 12′ withp-toluenesulfonyl chloride or another substituted or unsubstituted alkylor aryl sulfonyl chloride in the presence of a base, such as, forexample, triethylamine, provides the primary tosylate, Compound 13′.Treatment with this tosylate with a nucleophile,3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ) in thepresence of a base, under conventional conditions, provides Compound19′. Conversion of Compound 19′ into nelfinavir can be accomplished,under conventional conditions, for example, by treatment withthiophenol.

[0151] Another embodiment of this invention, illustrated in Scheme VI,provides for the preparation of amino alcohol, 1, from fusedepoxy-tetrahydrofuran, 14. Treatment of 1 with (S)-α-methylbenzylamine,or another chiral amine, containing at least 97.5% of a singleenantiomer, results in the opening of the epoxide to provide a mixtureof diastereomeric Compounds 15′ and 16′. This reaction may be conductedusing an appropriate solvent such as a mixture of isopropyl amine andwater. Crystallization of the diastereomers selectively providesCompound 15′. De-protection of the benzyl moiety of Compound 15′ may beconducted using conventional procedures, e.g. hydrogenolysis (hydrogenin the presence of 5% palladium on carbon). The amino-alcohol, 1, ishygroscopic and is preferably isolated as a salt, for example, as thep-toluenesulfonic acid salt, 17.

[0152] Alternatively, the chiral amino-tetrahydrofuran, 1, may beprepared from the fused epoxy-tetrahydrofuran, 14, using aqueousammonia, an achiral reagent, to provide a mixture of racemic 1 and 1′,which may be resolved using conventional resolution techniques, asillustrated in Scheme VII. For example, the racemic amino-compound maybe treated with a chiral acid to form a mixture of diastereomeric salts,which may then be separated by crystallization or chromatography.Neutralization and extractive work-up provides diastereomerically pureamino-tetrahydrofuran, 1, and recovery of the chiral acid.

[0153] Chiral acids that may be used in the resolution of racemicamino-tetrahydrofuran, 1, include L-tartaric acid,(1R)-(−)-10-camphorsulfonic acid, L-2-pyrrolidone-5-carboxylic acid,(−)-di-O,O′-benzoyl-L-tartaric acid, (−)-mono-(1R)-methyl phthalate, S(+) mandelic acid, L-aspartic acid, (−)-di-O,O′-benzoyl-L-tartaric acidmono (dimethylamide), (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonicacid, L(−)-malic acid, and D(−)-quinic acid.

[0154] It is understood that the compounds described herein may exist indifferent forms, such as stable and metastable crystalline forms andisotropic and amorphous forms, all of which are included within thescope of this invention.

[0155] As used herein, the term “PHIQ” refers to the reagent3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline, “AMBC” refers tothe reagent 3-acetoxy-2-methylbenzoyl chloride, “MTBE” refers to thesolvent methyl t-butyl ether, “MIBK” refers to the solventmethylisobutyl ketone and “PNB” refers to a p-nitrobenzoyl moiety.

EXAMPLE 1

[0156] Synthesis of (3R, 4S) 4-Amino-tetrahydro-furan-3-oltoluene-4-sulfonic acid salt, 17

[0157] (S)-α-Methylbenzyl amine (304 g, 2.51 mol) and3,4-epoxytetrahydrofuran 14 (200 g, 2.32 mol) were dissolved in2-propanol (1 L) and water (1 L). The solution was heated to reflux,with stirring, for 18 hours. The 2-propanol (ca. 1 L) was removed underreduced pressure and water (1 L) was added. The resulting slurry wasstirred at room temperature for 16 hours and filtered. The white solidswere washed with water (500 mL), then dried in a vacuum oven at roomtemperature to constant weight to afford crude Compound 15′ (170.1 g).The crude material was recrystallized by dissolving the solids in2-propanol (354 mL) and heptane (1 L) at 60° C. The solution was seededat 55° C. with pure Compound 15′ and allowed to cool to room temperatureover 18 hours. The solids were filtered, washed with heptane (200 mL)and dried in a vacuum oven at room temperature to constant weight togive pure Compound 15′ (123.2 g, 26%).

[0158] A 2 L Parr flask was charged with the pure Compound 15′ (120.7g), 2-propanol (840 mL) and 5% palladium on carbon (12 g). The flask wasshaken at 26 psi of hydrogen gas for 44 hours. Additional 5% palladiumon carbon (6 g) was added and the mixture was shaken at 26 psi ofhydrogen gas for 20 hours. The mixture was filtered through Celite,which was washed with 2-propanol (200 mL). Filtration through Celite andwashing was repeated.

[0159] para-Toluenesulfonic acid (110.8 g) was added to the solution andthe solution was concentrated under reduced pressure to 1 L.Methyl-t-butyl ether (MTBE, 1.5 L) was added and the resulting solidswere filtered, washed with MTBE (250 mL) and dried in a vacuum oven at40° C. to constant weight to afford pure Compound 17 (138 g, 86%).

EXAMPLE 2

[0160] Synthesis of Acetic Acid3-(4R-hydroxy-tetrahydro-furan-3S-ylcarbamoyl)-2-methyl-phenyl Ester, 2′

[0161] The amine salt, 17 (25.0 g, 90.9 mmol) and AMBC(3-acetoxy-2-methylbenzoyl chloride, 20.4 g, 95.9 mmol) were slurried inethyl acetate (188 mL) at room temperature. With water bath cooling,triethylamine (25.9 mL, 186.1 mmol) was added at a rate sufficient tomaintain the temperature below 25° C. The slurry was stirred at roomtemperature for 1 hour 45 minutes to give 90.8 mmol of a suspension oftetrahydrofuran-amide, 2′.

EXAMPLE 3

[0162] Synthesis of(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2-methanesulfonyloxyethane,18′

[0163] The reaction product mixture of Example 2 (containing 90.8 mmolof tetrahydrofuran-amide 2′) was cooled in an ice/acetone bath andmethanesulfonyl chloride (17.6 mL, 227 mmol) was added in one portion.Triethylamine (19 mL, 136.2 mmol) was added dropwise at a ratesufficient to keep the internal temperature below 10° C. Aceticanhydride (129 mL, 1362 mmol) was added in one portion and the coolingbath was removed. Sulfuric acid (98%, 38 mL, 681 mmol) was added inthree portions at 15 minute intervals. The mixture was stirred at roomtemperature for 17 hours. A suspension of sodium bicarbonate (305 g,3632 mmol, 40 equiv.) in 1 liter of water was prepared. This wasoverlaid with ethyl acetate (250 mL). The reaction mixture from abovewas added to the sodium bicarbonate slurry dropwise over 2 hours. Thelayers were separated and the aqueous layer was washed with ethylacetate (200 mL). The combined organic layers were washed with saturatedsodium bicarbonate (200 mL) and brine (200 mL). The organic layer wasdried (MgSO₄), filtered and evaporated to give 90.8 mmol of an oil of18′.

EXAMPLE 4

[0164] Synthesis of (3S, 4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicAcid t-butylamide, 20′

[0165] The crude product of Example 3,(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2methanesulfonyloxyethane,18′ (1.98 kg, 3.30 mol) was suspended in a mixed solvent of methanol(6.50 L) and water (6.50 L), and (3S, 4aS,8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, 642 g, 2.62mol) and potassium carbonate (1.36 kg, 9.81 mol) were successivelyadded, which was followed by stirring at 50° C. for 5.5 hours. Water(6.50 L) was added to cool the reaction mixture to room temperature andthe resulting crystals were collected by filtration. These crudecrystals were again suspended in water (6.50 L), stirred, washed andcollected by filtration. The obtained crystals were re-suspended inmethyl isobutyl ketone (10.0 L) and the suspension was subjected toazeotropic dehydration. The resulting slurry was cooled to roomtemperature and crystals were collected by filtration to give 902 g(1.07 mol) of the title compound, as colorless crystals.

[0166] Other bases that are suitable for use in this reaction include,sodium carbonate, sodium hydroxide, potassium hydroxide and the like.This reaction may be conducted at a temperature of between −78° C. and100° C. in a suitable solvent or suitable solvent mixtures including,but not limited to alcoholic solvents (for example, methanol, ethanol,propanol, isopropanol, and the like), water, ethyl acetate, isopropylacetate, and the like. Preferably, the reaction is conducted asdescribed above.

EXAMPLE 5

[0167] Synthesis of (3S, 4aS,8aS)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl-amino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylicAcid t-butylamide, 19′

[0168] (3S, 4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (701 g, 1.53 mol), obtained as in Example 4, wassuspended in methyl isobutyl ketone (7.00 L), and thiophenol (314 mL,3.06 mol) and potassium hydrogencarbonate (76.6 g, 0.765 mol) wereadded. The mixture was heated to reflux for 12 hours under a nitrogenatmosphere. After the completion of the reaction, toluene (7.00 L) wasadded, and the precipitated crystals were collected by filtration andwashed with toluene. These crude crystals were washed in a mixed solventof acetone and water (1:1), with heating, to give 695 g (1.22 mol) ofthe title compound (80% yield) as colorless crystals.

[0169] While the invention has been described in terms of variouspreferred embodiments using specific examples, those skilled in the artwill recognize through routine experimentation that various changes andmodifications can be made without departing from the spirit and scope ofthe invention, as defined in the appended claims.

We claim:
 1. A method for the preparation of an oxazoline,

from a tetrahydrofuran

comprising treating the tetrahydrofuran, wherein R_(a) is —COR(1) andR_(b) is hydrogen, —COR(3), —SO₂R(2) or a suitable hydroxyl protectinggroup with an oxophilic electrophilic reagent in a manner that iseffective to provide the oxazoline, wherein R_(b) is hydrogen, —COR(3),—SO₂R(2) or a suitable hydroxyl protecting group and R_(a) is hydrogen,—COR(3) or —SO₂R(2); wherein R(1), R(2) and R(3) independently representa substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkylor heteroaryl group.
 2. The method according to claim 1, comprisingtreating the tetrahydrofuran with about 1 to about 20 molar equivalentsof the oxophilic electrophilic reagent.
 3. The method according to claim1, wherein said oxophilic electrophilic reagent comprises a combinationof about 1 to about 20 molar equivalents of a suitable acid and about 1to about 20 molar equivalents of a suitable acid anhydride, wherein theanhydride and the acid are used in a relative molar ratio of from about1:5 to about 5:1, respectively.
 4. The method according to claim 1,wherein said oxophilic electrophilic reagent comprises a combination ofabout 2 to about 20 molar equivalents of a suitable acid and about 2 toabout 20 molar equivalents of a suitable acid anhydride, wherein theanhydride and the acid are used in a relative molar ratio of from about1:1 to about 5:1, respectively.
 5. The method according to claim 1,wherein said oxophilic electrophilic reagent comprises about 7.5 molarequivalents of a suitable acid and 15 molar equivalents of a suitableacid anhydride.
 6. The method according to claim 1 wherein saidtetrahydrofuran is treated with an anhydride under acidic conditions toform said oxazoline.
 7. A method for the preparation of an oxazolinehaving the formula:

wherein R(1), R(2) and R(3) independently represent substituted orunsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl,said method comprising the steps of: (1) treating anamino-tetrahydrofuran, or a salt thereof, having the formula:

in a manner that is effective to convert said amino-tetrahydrofuran, ora salt thereof, to a tetrahydrofuran-amide, having the formula:

(2) treating the tetrahydrofuran-amide with a substituted orunsubstituted alkyl or aryl sulfonylating reagent to convert saidtetrahydrofuran-amide to an tetrahydrofuran amide-sulfonate having theformula:

comprising the step-wise treatment of the tetrahydrofuran-amide with atleast one molar equivalent amount of the sulfonylating reagent, followedby treatment with a base, wherein the molar equivalent amount of baseused in the treatment is less than the molar equivalent amount of thesulfonylating reagent, and (3) treating the tetrahydrofuranamide-sulfonate with an oxophilic electrophilic reagent in a manner thatis effective to convert said tetrahydrofuran amide-sulfonate to saidoxazoline.
 8. A method for the preparation of an oxazoline diol havingthe formula:

said method comprising the steps of: (1) treating anamino-tetrahydrofuran, or a salt thereof, having the formula:

in a manner that is effective to convert the amino-tetrahydrofuran, or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide with an oxophilic electrophilicreagent in a manner that is effective to convert saidtetrahydrofuran-amide to an oxazoline diester having the formula:

(3) hydrolyzing the oxazoline diester to said oxazoline diol; whereinR(1) and R(3) independently represent substituted or unsubstitutedalkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
 9. A method forthe preparation of an oxazoline diol having the formula:

comprising the steps of: (1) treating an amino-tetrahydrofuran or a saltthereof, having the formula:

in a manner that is effective to convert the amino-tetrahydrofuran or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide with a substituted orunsubstituted alkyl or aryl sulfonylating reagent, in a manner effectiveto convert said tetrahydrofuran-amide to a fusedtetrahydrofuranyloxazoline having the formula:

(3) hydrolyzing the fused tetrahydrofuranyloxazoline to atetrahydrofuran-amide having the formula:

(4) treating the tetrahydrofuran-amide with an oxophilic electrophilicreagent in a manner that is effective to convert saidtetrahydrofuran-amide to an oxazoline diester having the formula:

(5) hydrolyzing the oxazoline diester to said oxazoline diol; whereinR(1) and R(3) independently represent substituted or unsubstitutedalkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
 10. A methodfor the preparation of an oxazoline having the formula:

wherein R(1) is substituted or unsubstituted alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl, R(10) is a suitable hydroxyl protectinggroup and R(11) is H or substituted alkyl sulfonyl, comprising the stepsof (1) treating an amino-tetrahydrofuran or a salt thereof, having theformula:

in a manner that is effective to convert the amino-tetrahydrofuran or asalt thereof, to a tetrahydrofuran-hydroxy-amide having the formula:

(2) treating the tetrahydrofuran-hydroxy-amide in a manner effective toprotect the hydroxyl moiety of the hydroxy-amide to form a protectedtetrahydrofuran-amide, having the formula:

(3) treating the protected tetrahydrofuran-amide with an oxophilicelectrophilic reagent in a manner that is effective to convert saidtetrahydrofuran-amide to said protected oxazoline; wherein saidoxophilic electrophilic reagent is selected from an oxophilic Lewisacid, an oxophilic protic acid, or triflic anhydride.
 11. A method forthe preparation of nelfinavir comprising the steps of: (1) treating anamino-tetrahydrofuran, or a salt thereof, having the formula:

in a manner that is effective to convert the amino-tetrahydrofuran, or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide to convert saidtetrahydrofuran-amide to a tetrahydrofuran amide-sulfonate having theformula:

comprising the step-wise treatment of the tetrahydrofuran-amide with atleast one molar equivalent amount of the sulfonylating reagent, followedby treatment with a base, wherein the molar equivalent amount of baseused in the treatment is less than the molar equivalent amount of thesulfonylating reagent, and (3) treating the tetrahydrofuran-amidesulfonate with an oxophilic electrophilic reagent in a manner that iseffective to convert said tetrahydrofuran amide-sulfonate to anoxazoline having the formula:

(4) treating the oxazoline in a manner that is effective to convert saidoxazoline to a compound having the formula:

(5) converting said compound to nelfinavir; wherein R(2) and R(3) areindependently selected from substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl or heteroaryl, and R(5) is a substituted orunsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein eachalkyl or aryl moiety may be substituted or unsubstituted.
 12. A methodfor the preparation of nelfinavir comprising the steps of: (1) treatingan amino-tetrahydrofuran or a salt thereof, having the formula:

in a manner that is effective to convert the amino-tetrahydrofuran or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide with an oxophilic electrophilicreagent in a manner that is effective to convert saidtetrahydrofuran-amide to an oxazoline triester having the formula:

(3) hydrolyzing the oxazoline triester to an oxazoline triol having theformula:

(4) protecting the oxazoline triol with a suitable hydroxyl protectinggroup, in a manner that is effective to convert said oxazoline triol toa di-protected oxazoline having the formula:

(5) treating the di-protected oxazoline with a substituted orunsubstituted alkyl or aryl sulfonylating reagent, in a manner effectiveto convert said oxazoline to a sulfonylated-di-protected oxazolinehaving the formula:

(6) treating the sulfonylated-di-protected oxazoline with3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner thatis effective to convert said oxazoline to a compound having the formula:

(7) converting said compound to nelfinavir; wherein R(2) and R(3) areindependently selected from substituted or unsubstituted alkyl, aryl,cycloalkyl, heterocycloalkyl or heteroaryl, R(5) is a substituted orunsubstituted HN-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein eachalkyl or aryl moiety may be substituted or unsubstituted, and R(7) isany suitable hydroxyl protecting group.
 13. A method for the preparationof nelfinavir comprising the steps of: (1) treating anamino-tetrahydrofuran, or a salt thereof, having the formula:

in a manner that is effective to convert the amino-tetrahydrofuran or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide with a substituted orunsubstituted alkyl or aryl sulfonylating reagent, in a manner effectiveto convert said tetrahydrofuran-amide to a fusedtetrahydrofuranyloxazoline having the formula:

(3) hydrolyzing the fused tetrahydrofuranyloxazoline to atetrahydrofuran-amide having the formula:

(4) treating the tetrahydrofuran-amide with an oxophilic electrophilicreagent in a manner that is effective to convert saidtetrahydrofuran-amide to an oxazoline triester having the formula:

(5) hydrolyzing the oxazoline triester to an oxazoline triol having theformula:

(6) treating the oxazoline triol with a substituted or unsubstitutedalkyl or aryl sulfonylating reagent, in a manner effective to convertsaid oxazoline to a protected oxazoline having the formula:

(7) treating the protected oxazoline with3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner thatis effective to convert said oxazoline to a compound having the formula:

(8) converting said compound to nelfinavir; wherein R(3) is selectedfrom substituted or unsubstituted alkyl, aryl, cycloalkyl,heterocycloalkyl or heteroaryl, R(5) is a substituted or unsubstitutedHN-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or arylmoiety may be substituted or unsubstituted, R(8) is a substituted orunsubstituted alkyl or aryl sulfonyl and R(9) is hydrogen or R(8).
 14. Amethod for the preparation of nelfinavir comprising the steps of: (1)treating an amino-tetrahydrofuran, or a salt thereof, having theformula:

in a manner that is effective to convert the amino-tetrahydrofuran or asalt thereof, to a tetrahydrofuran-amide having the formula:

(2) treating the tetrahydrofuran-amide in a manner that is effective toconvert the tetrahydrofuran-amide to a protected tetrahydrofuran-amide,having the formula:

(3) treating the protected tetrahydrofuran-amide with an oxophilicelectrophilic reagent selected from an oxophilic Lewis acid, anoxophilic protic acid, or triflic anhydride in a manner that iseffective to convert the tetrahydrofuran-amide to a protected oxazolinehaving the formula:

(4) treating the protected oxazoline with3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner thatis effective to convert said oxazoline to a compound having the formula:

(5) converting said compound to nelfinavir; wherein R(1) is substitutedor unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl orheteroaryl, R(5) is a substituted or unsubstituted NH-alkyl, NH-aryl,O-alkyl, or O-aryl group, wherein each alkyl or aryl moiety may besubstituted or unsubstituted, R(10) is a suitable hydroxyl protectinggroup and R(11) is H or substituted alkyl sulfonyl.
 15. The methodaccording to any one of claims 1 to 10 wherein R(1)is CF₃, a substitutedor unsubstituted phenyl, or a C₁-C₆ alkyl.
 16. The method according toany one of claims 1 to 10 wherein R(11) is


17. The method according to any one of claims 7 to 9 or 11 to 13,comprising treating the tetrahydrofuran with about 1 to about 20 molarequivalents of the oxophilic electrophilic reagent.
 18. The methodaccording to any one of claims 7 to 9 or 11 to 13, wherein saidoxophilic electrophilic reagent comprises a combination of about 1 toabout 20 molar equivalents of a suitable acid and about 1 to about 20molar equivalents of a suitable acid anhydride, wherein the anhydrideand the acid are used in a relative molar ratio of from about 1:5 toabout 5:1, respectively.
 19. The method according to any one of claims 7to 9 or 11 to 13, wherein said oxophilic electrophilic reagent comprisesa combination of about 2 to about 20 molar equivalents of a suitableacid and about 2 to about 20 molar equivalents of a suitable acidanhydride, wherein the anhydride and the acid are used in a relativemolar ratio of from about 1:1 to about 5:1, respectively.
 20. The methodaccording to any one of claims 7 to 9 or 11 to 13, wherein saidoxophilic electrophilic reagent comprises about 7.5 molar equivalents ofa suitable acid and 15 molar equivalents of a suitable acid anhydride.21. The method according to any one of claims 7 to 9 or 11 to 13,wherein R(3) is methyl or phenyl.
 22. The method according to any one ofclaims 7 to 9 or 11 to 13, wherein said tetrahydrofuran-amide is treatedwith acetic anhydride and sulfuric acidic to form said oxazoline. 23.The method according to claim 15 wherein R(3) is methyl.
 24. The methodaccording to any one of claims 7 to 10, wherein theamino-tetrahydrofuran is treated with an compound having the formulaR(1)COX, wherein X is chloro or bromo, to form the tetrahydrofuran-amideand R(1) is


25. The method according to claims 11 to 14 wherein R(5) is HN-t-Bu. 26.The method according to claim 12, wherein R(7) is trialkylsilyl,dialkyl-monoarylsilyl, diaryl-monoalkylsilyl, substituted orunsubstituted aroyl or alkanoyl.
 27. The method according to claim 12,wherein R(7) is trimethylsilyl, tert-butyl-di-methylsilyl, benzoyl, orpara-nitrobenzoyl.
 28. The method according to claim 12, wherein R(7) isa para-nitrobenzoyl.
 29. The method according to claim 13, wherein R(8)is a substituted or unsubstituted alkyl or aryl sulfonyl. 30 The methodaccording to claim 13, wherein R(8) is p-toluenesulfonyl.
 31. A methodof the preparation of a chiral amino-tetrahydrofuran, 1, or a saltthereof:

said method comprising the steps of: (1) treating anepoxy-tetrahydrofuran having the formula:

with an aminating reagent to form a stereoisomeric mixture ofamino-tetrahydrofurans having the formulae:

(2) treating the amino-tetrahydrofuran mixture in a manner effective toseparate the amino-tetrahydrofuran stereoisomers, and (3) isolating theamino-tetrahydrofuran, 1, or a salt thereof; wherein R(6) is hydrogen ora suitable nitrogen protecting group.
 32. The method according to claim31, wherein the amino-tetrahydrofuran, 1, is substantiallyenantiomerically pure.
 33. The method according to claim 31, whereinR(6) is a substituted or unsubstituted alkanoyl, aroyl,arylalkylcarbonyl, arylalkyl, heteroarylalkyl, wherein the alkyl, arylor heteroaryl is substituted or unsubstituted.
 34. The method accordingto claim 31, wherein the aminating reagent is a chiral aminatingreagent.
 35. The method according to claim 34, wherein R(6) is


36. The method according to claim 34, comprising separating theamino-tetrahydrofuran stereoisomers by crystallization orchromatography.
 37. The method according to claim 36, further comprisingremoving the R(6) substituent from the separated amino-tetrahydrofuranstereoisomers.
 38. The method according to claim 31, wherein theaminating reagent is an achiral aminating reagent.
 39. The methodaccording to claim 38 further comprising treating theamino-tetrahydrofuran mixture with a chiral auxiliary reagent to producediastereomeric amino-tetrahydrofurans.
 40. The method according to claim39, comprising separating the amino-tetrahydrofuran diastereomers bycrystallization or chromatography.
 41. The method according to claim 40,further comprising removing the chiral auxiliary reagent from theseparated amino-tetrahydrofuran stereoisomers.